Schizophrenia is recognized as a major health problem in this country and the world. The mesolimbic dopamine system, which has neuronal perikarya in the ventral tegmental area and axonal terminals in the nucleus accumbens, has been postulated to have a pathogenic role in schizophrenia. In addition to dopamine, the ventral tegmental area and nucleus accumbens contain a variety of other putative neurotransmitters, including; acetylcholine, Gamma-aminobutyric acid, cholecystokining, enkephalin, neurotensin substance P and thyrotropin-releasing hormone. This poses the possibility that these substances may modulate mesolimbic dopaminergic function, and thereby play a role in schizophrenia. I have outlined experiments in this proposal which will evaluate the capacity of these putative neurotransmitters to modulate the mesolimbic dopamine system. This will be performed by acute microinjection of the compound of interest into the ventral tegmental area and/or nucleus accumbens of the rat. After microinjection, I will assess effects on the mesolimbic dopamine system by neurochemical measurements of dopamine release, synthesis and turnover, and by behavioral measurements of locomotion and rearing. Compounds found to alter mesolimbic dopaminergic function will be chronically injected into the ventral tegmental area or nucleus accumbens, and neurochemical and behavioral changes monitored. Concurrent with these studies, I will conduct anatomical experiments employing immunohistochemistry which will provide a detailed light microscopic map of the location of putative neurotransmitter systems relative to the mesolimbic dopamine system. Further, retrograde transport of horseradish peroxidase coupled with immunohistochemistry will be used to define the neurochemical nature of afferents to the mesolimbic system. These studies can provide insight into the neurobiology of schizophrenia by evaluating how endogenous neurotransmitter systems affect the mesolimbic dopamine system. Further, compounds found to decrease mesolimbic dopaminergic function may ultimately provide a new generation of psychopharmacological therapy in the treatment of schizophrenia.